Prostate cancer (PCa) incidence and mortality rate is higher in African-American (AA) men than in Caucasian Americans (CAs). AA men with PCa also present with higher tumor volume, more advanced tumor stage, and higher Gleason grade. Prostate carcinogenesis and tumor progression are related highly to the expression and activity of the androgen receptor (AR). Mutations, genomic amplification, and polymorphisms in the CAG/GGC repeat also can increase AR expression and/or activity. In CAs, AR mutations are infrequent (<1%) in localized tumors, but occur at a higher frequency in advanced, metastatic, or hormone-refractory disease. In AAs, the prevalence of AR mutations and their prognostic significances in primary PCa are unknown. We discovered genomic amplification and somatic mutation of AR in a PCa cell line established by our laboratory from an AA patient with localized PCa. In addition, in a set of 41 radical prostatectomy samples (25 AAs and 16 CAs), we identified 4 AR mutations, 3 somatic and 1 germline in AA patients. These data led us to hypothesize that AR mutations in primary African-American PCa may be more frequent than expected and may contribute to disease aggressiveness or serve as a prognostic factor. We propose the following Specific Aims: Aim 1: Determine the prevalence of AR mutations in primary African-Americans PCa. Exon-specific primers of the AR gene will be used to sequence genomic-DNA extracted from laser-captured cells of paraffin- embedded tissue sections of radical prostatectomy specimens to determine the prevalence of somatic AR mutations in 250 AA patients with primary untreated PCa. Aim 2: Determine the contribution of AR mutation to PCa heterogeneity in African-Americans. Clinical and histopathological heterogeneity of PCa present a major challenge to therapeutic interventions. Differences in AR expression and microvascular density are considered as the two major contributors to PCa heterogeneity. We will use flow cytometry and immunohistochemical staining to examine AR and microvessel density in AA PCa with mutated AR. Aim 3: Define the prognostic significance of AR mutations in primary African-American PCa. We will determine the prognostic significance of AR mutations alone or in combination with AR and PSA polymorphic sites in relation to prognostic clinical or histopathological variables including family history, age, PSA, 5 year PSA-free survival, primary Gleason pattern, Gleason sum, and TNM stage. Significance: The results of this exploratory (R21) project will provide both the prevalence and prognostic value of AR mutations and may help us to understand better and address more effectively the racial disparity of the aggressiveness of PCa in AAs when compared to Caucasians. PUBLIC HEALTH RELEVANCE: The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African-American (AA) men are higher than in Caucasians. To understand and address the racial disparity of the disease aggressiveness, reliable prognostic factors are needed. Our discovery of a high frequency of androgen receptor mutations in untreated localized AA PCa might have prognostic significance that would provide us a more effective therapeutic approach.